1. Field of the Invention
Embodiments of the present invention relate generally to the field of treating addictions such as opioid drug additions. In particular, the present invention relates to a novel high drug loaded injectable microparticle, such as a microsphere or microcapsule (if a coating is included), including one or more active ingredients, such as an opioid agonist and/or partial opioid agonist compound. The novel microparticles are administered in a manner to promote the gradual release of an active ingredient, such as a drug, over an effective time period so as to serve as a treatment regimen for opioid dependent individuals.
2. Description of Related Art
Addiction to opioid drugs (opioids) by an individual is characterized by a dependence syndrome having both a strong psychological dependent aspect and a strong physical dependent aspect. The psychological dependent aspect typically is manifested by an overpowering compulsion on the part of the addict to continue taking opioids. This compulsion may be motivated in part by the development of a tolerance to opioids generally so that although one opioid may be substituted for another, the dosage of any opioid taken must be continually increased in order to obtain the initial psychological effect such as euphoria. Typically, an acute intoxication with opioids is characterized by euphoria, flushing, itching of the skin, miosis, drowsiness, decreased respiratory rate and depth, hypotension, bradycardia, and decreased body temperature.
Withdrawal of the drug or administration of an antagonist provokes a well known abstinence or withdrawal syndrome. Such a withdrawal syndrome generally includes symptoms and signs opposite to the drug's pharmacologic effects, e.g., central nervous system (CNS) hyperactivity. The severity of the withdrawal syndrome increases both with the size of the opioid dose used by the addict and the length of time the addict has used the opioid drug. Accordingly, a physical and/or psychological dependence on opioids develops to prevent experiencing the discomfort of the abstinence or withdrawal syndrome. In the case of heroin addiction, symptoms of withdrawal syndrome typically begin to appear as early as 4 to 6 hours after withdrawal (abstinence) from drug intake and reach a peak of severity within 36 to 72 hours. An initial anxiety and craving for the drug are followed by other symptoms of increasing severity and intensity. A characteristic early sign of withdrawal syndrome in addicted humans is an increased resting respiratory rate, >16/min, usually accompanied by yawning, perspiration, lacrimation, rhinorrhea, mydriasis, piloerection, tremors, muscle twitches, hot and cold flashes, aching muscles, and anorexia.
Tolerance and physical dependence on opioids can develop rapidly. For example, therapeutic doses of opioids, e.g., morphine, taken regularly over a 2- to 3-day period can lead to tolerance and physical dependence so that the user may show symptoms of withdrawal when the drug is discontinued.
Opioid drug use also induces cross-tolerance toward other opioid drugs, although such cross-tolerance may vary in degree from one opioid to another. Nevertheless, this property is the reason that addicts may substitute one opioid for another.
Various methods of treating addiction to opioid type drugs in individuals have been devised. A number of methods and compounds have been purported to be useful in treating the addict. For example, agonists are compounds that mimic the opioid and purportedly are useful in treating psychological dependence (tolerance) or physical dependence. Opioid agonists include methadone, buprenorphine and dopamine agonists, such as bromocriptine mesylate (see, U.S. Pat. No. 4,935,429). In the well known methadone substitution maintenance programs for heroin addiction, the heroin agonist methadone is administered orally at a dose that prevents substantial withdrawal syndrome and craving for opioid drugs. An attempt is then made to decrease the addict's dependence on the orally administered methadone. However, such weaning from orally administered methadone may, itself, be extremely difficult. Furthermore, addicts in such programs may abuse the use of the methadone, for example, by combining it with other drugs, and thereby simply transfer their heroin addiction to a methadone-based addiction.
A few compounds have been reported to act as antagonists of opioid addiction, for example, naloxone and naltrexone (see, e.g., O'Brien, C. P., et al., In Problems of Drug Dependence, 1982, NIDA Research Monograph 43, pages 71–78 (Harris, L. S., ed.) (DHHS Pub. (ADM) 82–1264, 1983); Rawson, R. A., et al., In Problems of Drug Dependence 1983, NIDA Research Monograph 49, pages 289–295 (Harris, L. S., ed.) (DHHS Pub. (ADM) 84–1316, 1984); Nuwayser, E. S., et al., Proc. Intern. Symp. Control. Rel. Bioact. Mater., 15: 201–202 (1988)); buprenorphine (at certain concentrations) and spiroindane opiate analogs (U.S. Pat. No. 5,298,622). The primary uses of opioid antagonists have been in research and in therapies to reverse the toxic effects of opioids in cases of overdose. Such antagonists purportedly can bind to opioid receptors in the brain and thereby block the euphoric effect of opioids. Naltrexone is the only opioid antagonist currently approved by the Federal Drug Administration for use in the United States as a treatment of post addicts. Typically, the antagonist naltrexone is administered orally three times per week. Thus, as with methadone maintenance programs, regimens utilizing antagonists require the addict voluntarily to adhere to a rigidly controlled schedule of multiple administrations. Requiring the opioid addict strictly to adhere to a schedule of multiple administrations of a therapeutic compound over an indefinite period of time may be too onerous for most addicts to endure and may account for the fact that the current methods of treating opioid addiction have not proven to be widely successful at promoting a psychological and physical independence.
Microsphere compositions including naltrexone disclosed for use in reducing consumption of heroin and alcohol are known. See U.S. Pat. No. 6,306,425 hereby incorporated by reference in its entirety for all purposes. However, such microsphere compositions include less than 50% by weight of naltrexone, and therefore require large volumes of injectable formulations when treating drug addicted individuals. The formulations contemplate multiple administrations of the microspheres.
Accordingly, a need exists to provide a high drug loaded delivery vehicle for use in drug treatment programs. Such a high drug loaded delivery vehicle can provide a sustained release of an active ingredient over a prolonged period of time sufficient to reduce the withdrawal symptoms of opioid drug addicts and promote psychological and physical independence from the opioid drug.